Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives
Abstract
1. Introduction
2. Results and Discussion
2.1. Docking Studies
2.2. Prediction of Pharmacokinetic Properties by SwissADME
3. Materials and Methods
3.1. Experimental Procedures
3.2. General Procedure for the Synthesis of Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione Derivatives 3a–p
3.3. NMR Spectra
3.3.1. (2R*,4aR*,5R*,8S*,8aS*)-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3a)
3.3.2. (2R*,4aR*,5R*,8S*,8aS*)-5′-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3b)
3.3.3. (2R*,4aR*,5R*,8S*,8aS*)-5′-iodo-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3c)
3.3.4. (2R*,4aR*,5R*,8S*,8aS*)-7′-chloro-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3d)
3.3.5. (2S*,4aS*,5R*,8S*,8aR*)-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3e)
3.3.6. (2S*,4aS*,5R*,8S*,8aR*)-5′-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3f)
3.3.7. (2S*,4aS*,5R*,8S*,8aR*)-5′-iodo-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3g)
3.3.8. (4aS*,5R*,8S*,8aR*)-7′-chloro-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3h*)
3.3.9. (2R*,4aR*,5R*,8S*,8aS*)-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3i)
3.3.10. (2R*,4aR*,5R*,8S*,8aS*)-3,5′-dimethyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3j)
3.3.11. (2R*,4aR*,5R*,8S*,8aS*)-5′-iodo-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3k)
3.3.12. (4aR*,5R*,8S*,8aS*)-7′-chloro-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3l*)
3.3.13. (2S*,4aS*,5R*,8S*,8aR*)-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3m)
3.3.14. (4aS*,5R*,8S*,8aR*)-3,5′-dimethyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3n*)
3.3.15. (4aS*,5R*,8S*,8aR*)-5′-iodo-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3o*)
3.3.16. (4aS*,5R*,8S*,8aR*)-7′-chloro-3-methyl-4a,5,8,8a-tetrahydro-1H-spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4(3H)-dione (3p*)
3.3.17. (1R*,2R*,3S*,4S*)-3-((Z)-(5-methyl-2-oxoindolin-3-ylidene)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (Bb)
3.3.18. (1R*,2R*,3S*,4S*)-3-((Z)-(7-chloro-2-oxoindolin-3-ylidene)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (Bd)
3.4. Docking Studies
3.5. SwissADME Predictions
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Dhokne, P.; Sakla, A.P.; Shankaraiah, N. Structural Insights of Oxindole Based Kinase Inhibitors as Anticancer Agents: Recent Advances. Eur. J. Med. Chem. 2021, 216, 113334. [Google Scholar] [CrossRef]
- Zhang, J.; Zhao, J.; Wang, L.; Liu, J.; Ren, D.; Ma, Y. Design, Synthesis and Docking Studies of Some Spiro-Oxindole Dihydroquinazolinones as Antibacterial Agents. Tetrahedron 2016, 72, 936–943. [Google Scholar] [CrossRef]
- Mane, R.; Yaraguppi, D.A.; Ashok, A.K.; Gangadharappa, B.; Chandrakala, K.B.; Kamanna, K. Glutamic Acid-Catalyzed Synthesis of Dihydroquinazolinone: Anticancer Activity, Electrochemical Behavior, Molecular Docking, Dynamics, Simulations and Drug-Likeness Studies. Res. Chem. Intermed. 2024, 50, 3271–3303. [Google Scholar] [CrossRef]
- Saraswat, P.; Jeyabalan, G.; Hassan, M.Z.; Rahman, M.U.; Nyola, N.K. Review of Synthesis and Various Biological Activities of Spiro Heterocyclic Compounds Comprising Oxindole and Pyrrolidine Moities. Synth. Commun. 2016, 46, 1643–1664. [Google Scholar] [CrossRef]
- Kaur, M.; Singh, M.; Chadha, N.; Silakari, O. Oxindole: A Chemical Prism Carrying Plethora of Therapeutic Benefits. Eur. J. Med. Chem. 2016, 123, 858–894. [Google Scholar] [CrossRef] [PubMed]
- Huang, X.; Wang, H.; Cao, Q.; Li, Y.; Zhang, J. Access to 3,3-Disubstituted Oxindoles via Microwave-Assisted Cannizzaro and Aldol Reactions of Formaldehyde with Isatins and Their Imines. RSC Adv. 2021, 11, 17320–17323. [Google Scholar] [CrossRef]
- Liu, Y.; Gao, P.; Wang, J.; Sun, Q.; Ge, Z.; Li, R. Primary 1,2-Diamine Catalysis (V): Efficient Asymmetric Aldol Reactions of Isatins with Cyclohexanone. Synlett 2012, 23, 1031–1034. [Google Scholar] [CrossRef]
- Lv, X.-X.; Liu, N.; Chen, F.; Zhang, H.; Du, Z.-H.; Wang, P.; Yuan, M.; Da, C.S. Highly Asymmetric Aldol Reaction of Isatins and Ketones Catalyzed by Chiral Bifunctional Primary-Amine Organocatalyst on Water. Org. Biomol. Chem. 2023, 21, 8695–8701. [Google Scholar] [CrossRef]
- Klumpp, D.A.; Yeung, K.Y.; Prakash, G.K.S.; Olah, G.A. Preparation of 3,3-Diaryloxindoles by Superacid-Induced Condensations of Isatins and Aromatics with a Combinatorial Approach. J. Org. Chem. 1998, 63, 4481–4484. [Google Scholar] [CrossRef]
- Rokade, B.V.; Guiry, P.J. Synthesis of α-Aryl Oxindoles by Friedel–Crafts Alkylation of Arenes. J. Org. Chem. 2020, 85, 6172–6180. [Google Scholar] [CrossRef]
- Vinoth, N.; Lalitha, A. Catalyst-Free Three-Component Synthesis, Antibacterial, Antifungal, and Docking Studies of Spiroindoline Derivatives. Polycyclic Aromat. Compd. 2022, 42, 517–533. [Google Scholar] [CrossRef]
- Cheng, X.; Vellalath, S.; Goddard, R.; List, B. Direct Catalytic Asymmetric Synthesis of Cyclic Aminals from Aldehydes. J. Am. Chem. Soc. 2008, 130, 15786–15787. [Google Scholar] [CrossRef] [PubMed]
- Kinsella, M.; Duggan, P.G.; Lennon, C.M. Screening of Simple N-Aryl and N-Heteroaryl Pyrrolidine Amide Organocatalysts for the Enantioselective Aldol Reaction of Acetone with Isatin. Tetrahedron: Asymmetry 2011, 22, 1423–1433. [Google Scholar] [CrossRef]
- Gavendova, M.; Lennon, C.M.; Coffey, L.; Manesiotis, P.; Kinsella, M. Novel β -amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles. ChemistrySelect 2019, 4, 8246–8254. [Google Scholar] [CrossRef]
- Dabiri, M.; Mohammadi, A.A.; Qaraat, H. An Efficient and Convenient Protocol for the Synthesis of Novel 1′H-Spiro[Isoindoline-1,2′-Quinazoline]-3,4′(3′H)-Dione Derivatives. Monatsh Chem 2009, 140, 401–404. [Google Scholar] [CrossRef]
- Mustaque, K.M.; Subramani, A.; Shabeer, T.K.; Thajudeen, H.; Ahamed, V.S.J. Amino Acid Catalyzed Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives. LOC 2018, 15, 246–250. [Google Scholar] [CrossRef]
- Shaabani, A.; Maleki, A.; Mofakham, H. Click Reaction: Highly Efficient Synthesis of 2,3-Dihydroquinazolin-4(1 H)-Ones. Synth. Commun. 2008, 38, 3751–3759. [Google Scholar] [CrossRef]
- Revathy, K.; Lalitha, A. P-TSA-Catalyzed Synthesis of Spiroquinazolinones. J. Iran. Chem. Soc. 2015, 12, 2045–2049. [Google Scholar] [CrossRef]
- Safaei-Ghomi, J.; Teymuri, R. A Three-component Process for the Synthesis of 2,3-dihydroquinazolin-4(1H)-one Derivatives Using Nanosized Nickel Aluminate Spinel Crystals as Highly Efficient Catalysts. J. Chin. Chem. Soc. 2019, 66, 1490–1498. [Google Scholar] [CrossRef]
- Narasimhulu, M.; Lee, Y.R. Ethylenediamine Diacetate-Catalyzed Three-Component Reaction for the Synthesis of 2,3-Dihydroquinazolin-4(1H)-Ones and Their Spirooxindole Derivatives. Tetrahedron 2011, 67, 9627–9634. [Google Scholar] [CrossRef]
- Mane, M.M.; Pore, D.M. Sulfamic Acid as Energy Efficient Catalyst for Synthesis of Flurophores, 1-H-Spiro [Isoindoline-1,2′-Quinazoline]-3,4′(3′H)-Diones. J. Chem. Sci. 2016, 128, 657–662. [Google Scholar] [CrossRef]
- Fallah-Mehrjardi, M.; Kalantari, S. A Brønsted Acid Ionic Liquid Immobilized on Fe3O4@SiO2 Nanoparticles as an Efficient and Reusable Solid Acid Catalyst for the Synthesis of 2,3-Dihydroquinazolin-4(1H)-Ones. Russ. J. Org. Chem. 2020, 56, 298–306. [Google Scholar] [CrossRef]
- Subba Reddy, B.V.; Venkateswarlu, A.; Madan, C.; Vinu, A. Cellulose-SO3H: An Efficient and Biodegradable Solid Acid for the Synthesis of Quinazolin-4(1H)-Ones. Tetrahedron Lett. 2011, 52, 1891–1894. [Google Scholar] [CrossRef]
- Rambabu, D.; Raja, G.; Yogi Sreenivas, B.; Seerapu, G.P.K.; Lalith Kumar, K.; Deora, G.S.; Haldar, D.; Rao, M.V.B.; Pal, M. Spiro Heterocycles as Potential Inhibitors of SIRT1: Pd/C-Mediated Synthesis of Novel N-Indolylmethyl Spiroindoline-3,2′-Quinazolines. Bioorg. Med. Chem. Lett. 2013, 23, 1351–1357. [Google Scholar] [CrossRef]
- Hemalatha, K.; Madhumitha, G.; Vasavi, C.S.; Munusami, P. 2,3-Dihydroquinazolin-4(1H)-Ones: Visible Light Mediated Synthesis, Solvatochromism and Biological Activity. J. Photochem. Photobiol. B 2015, 143, 139–147. [Google Scholar] [CrossRef]
- Novanna, M.; Kannadasan, S.; Shanmugam, P. Phosphotungstic Acid Mediated, Microwave Assisted Solvent-Free Green Synthesis of Highly Functionalized 2′-Spiro and 2,3-Dihydro Quinazolinone and 2-Methylamino Benzamide Derivatives from Aryl and Heteroaryl 2-Amino Amides. Tetrahedron Lett. 2019, 60, 201–206. [Google Scholar] [CrossRef]
- Ghosh, S.K.; Nagarajan, R. Deep Eutectic Solvent Mediated Synthesis of Quinazolinones and Dihydroquinazolinones: Synthesis of Natural Products and Drugs. RSC Adv. 2016, 6, 27378–27387. [Google Scholar] [CrossRef]
- Ramesh, R.; Nagasundaram, N.; Meignanasundar, D.; Vadivel, P.; Lalitha, A. Glycerol Assisted Eco-Friendly Strategy for the Facile Synthesis of 4,4′-(Arylmethylene)Bis(3-Methyl-1H-Pyrazol-5-Ols) and 2-Aryl-2,3-Dihydroquinazolin-4(1H)-Ones under Catalyst-Free Conditions. Res. Chem. Intermed. 2017, 43, 1767–1782. [Google Scholar] [CrossRef]
- Jiang, Y.; Liu, Y.; Tu, S.-J.; Shi, F. Enantioselective Synthesis of Biologically Important Spiro[Indoline-3,2′-Quinazolines] via Catalytic Asymmetric Isatin-Involved Tandem Reactions. Tetrahedron: Asymmetry 2013, 24, 1286–1296. [Google Scholar] [CrossRef]
- Wang, L.; Jiang, T.; Li, P.; Sun, R.; Zuo, Z. Asymmetric Syntheses of Spirooxindole-dihydroquinazolinones by Cyclization Reactions between N-substituted Anthranilamides and Isatins. Adv. Synth. Catal. 2018, 360, 4832–4836. [Google Scholar] [CrossRef]
- Nakamura, S.; Wada, T.; Takehara, T.; Suzuki, T. Catalytic Enantioselective Synthesis of N, N -Acetals from α-Dicarbonyl Compounds Using Chiral Imidazoline-Phosphoric Acid Catalysts. Adv. Synth. Catal. 2020, 362, 5374–5379. [Google Scholar] [CrossRef]
- Bergman, J.; Arewång, C.-J.; Svensson, P.H. Oxidative Ring Expansion of Spirocyclic Oxindole Derivatives. J. Org. Chem. 2014, 79, 9065–9073. [Google Scholar] [CrossRef] [PubMed]
- Ötvös, S.B.; Georgiádes, Á.; Mészáros, R.; Kis, K.; Pálinkó, I.; Fülöp, F. Continuous-Flow Oxidative Homocouplings without Auxiliary Substances: Exploiting a Solid Base Catalyst. J. Catal. 2017, 348, 90–99. [Google Scholar] [CrossRef]
- Bisht, G.S.; Dunchu, T.D.; Gnanaprakasam, B. Synthesis of Quaternary Spirooxindole 2H -Azirines under Batch and Continuous Flow Condition and Metal Assisted Umpolung Reactivity for the Ring-Opening Reaction. Chem. Asian J. 2021, 16, 656–665. [Google Scholar] [CrossRef]
- Liu, D.; Xu, H. Electrochemical Rearrangement of Indoles to Spirooxindoles in Continuous Flow. Eur. J. Org. Chem. 2023, 26, e202200987. [Google Scholar] [CrossRef]
- Stolle, A.; Szuppa, T.; Leonhardt, S.E.S.; Ondruschka, B. Ball Milling in Organic Synthesis: Solutions and Challenges. Chem. Soc. Rev. 2011, 40, 2317–2329. [Google Scholar] [CrossRef]
- James, S.L.; Adams, C.J.; Bolm, C.; Braga, D.; Collier, P.; Friščić, T.; Grepioni, F.; Harris, K.D.M.; Hyett, G.; Jones, W.; et al. Mechanochemistry: Opportunities for New and Cleaner Synthesis. Chem. Soc. Rev. 2012, 41, 413–447. [Google Scholar] [CrossRef]
- Rodríguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C. Solvent-Free Carbon-Carbon Bond Formations in Ball Mills. Adv. Synth. Catal. 2007, 349, 2213–2233. [Google Scholar] [CrossRef]
- Miklós, F.; Hum, V.; Fülöp, F. Eco-Friendly Syntheses of 2,2-Disubstituted- and 2-Spiroquinazolinones. Arkivoc 2014, 2014, 25–37. [Google Scholar] [CrossRef]
- Zhang, J.; Liu, J.; Ma, Y.; Ren, D.; Cheng, P.; Zhao, J.; Zhang, F.; Yao, Y. One-Pot Synthesis and Antifungal Activity against Plant Pathogens of Quinazolinone Derivatives Containing an Amide Moiety. Bioorg. Med. Chem. Lett. 2016, 26, 2273–2277. [Google Scholar] [CrossRef]
- Gamal Al-kaf, A. Introductory Chapter: The Newest Research in Quinazolinone and Quinazoline Derivatives. In Quinazolinone and Quinazoline Derivatives; Gamal Al-kaf, A., Ed.; IntechOpen: London, UK, 2020; ISBN 978-1-83880-139-7. [Google Scholar]
- Dutta, A.; Sarma, D. Recent Advances in the Synthesis of Quinazoline Analogues as Anti-TB Agents. Tuberculosis 2020, 124, 101986. [Google Scholar] [CrossRef] [PubMed]
- Pettus, L.H.; Andrews, K.L.; Booker, S.K.; Chen, J.; Cee, V.J.; Chavez, F.; Chen, Y.; Eastwood, H.; Guerrero, N.; Herberich, B.; et al. Discovery and Optimization of Quinazolinone-Pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors. J. Med. Chem. 2016, 59, 6407–6430. [Google Scholar] [CrossRef] [PubMed]
- Dohle, W.; Jourdan, F.L.; Menchon, G.; Prota, A.E.; Foster, P.A.; Mannion, P.; Hamel, E.; Thomas, M.P.; Kasprzyk, P.G.; Ferrandis, E.; et al. Quinazolinone-Based Anticancer Agents: Synthesis, Antiproliferative SAR, Antitubulin Activity, and Tubulin Co-Crystal Structure. J. Med. Chem. 2018, 61, 1031–1044. [Google Scholar] [CrossRef]
- Hamiaux, C.; Larsen, L.; Lee, H.W.; Luo, Z.; Sharma, P.; Hawkins, B.C.; Perry, N.B.; Snowden, K.C. Chemical Synthesis and Characterization of a New Quinazolinedione Competitive Antagonist for Strigolactone Receptors with an Unexpected Binding Mode. Biochem. J. 2019, 476, 1843–1856. [Google Scholar] [CrossRef] [PubMed]
- Gero, T.W.; Heppner, D.E.; Beyett, T.S.; To, C.; Azevedo, S.C.; Jang, J.; Bunnell, T.; Feru, F.; Li, Z.; Shin, B.H.; et al. Quinazolinones as Allosteric Fourth-Generation EGFR Inhibitors for the Treatment of NSCLC. Bioorg. Med. Chem. Lett. 2022, 68, 128718. [Google Scholar] [CrossRef]
- Iwashita, A.; Hattori, K.; Yamamoto, H.; Ishida, J.; Kido, Y.; Kamijo, K.; Murano, K.; Miyake, H.; Kinoshita, T.; Warizaya, M.; et al. Discovery of Quinazolinone and Quinoxaline Derivatives as Potent and Selective Poly(ADP-ribose) Polymerase-1/2 Inhibitors. FEBS Lett. 2005, 579, 1389–1393. [Google Scholar] [CrossRef]
- Bouley, R.; Kumarasiri, M.; Peng, Z.; Otero, L.H.; Song, W.; Suckow, M.A.; Schroeder, V.A.; Wolter, W.R.; Lastochkin, E.; Antunes, N.T.; et al. Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-Cyanostyryl)Quinazolin-4(3H)-One. J. Am. Chem. Soc. 2015, 137, 1738–1741. [Google Scholar] [CrossRef]
- Janardhanan, J.; Bouley, R.; Martínez-Caballero, S.; Peng, Z.; Batuecas-Mordillo, M.; Meisel, J.E.; Ding, D.; Schroeder, V.A.; Wolter, W.R.; Mahasenan, K.V.; et al. The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus Aureus. Antimicrob. Agents Chemother. 2019, 63, e02637-18. [Google Scholar] [CrossRef]
- Wei, M.; Chai, W.-M.; Wang, R.; Yang, Q.; Deng, Z.; Peng, Y. Quinazolinone Derivatives: Synthesis and Comparison of Inhibitory Mechanisms on α-Glucosidase. Bioorg. Med. Chem. 2017, 25, 1303–1308. [Google Scholar] [CrossRef]
- Taayoshi, F.; Iraji, A.; Moazzam, A.; Soleimani, M.; Asadi, M.; Pedrood, K.; Akbari, M.; Salehabadi, H.; Larijani, B.; Adibpour, N.; et al. Synthesis, Molecular Docking, and Cytotoxicity of Quinazolinone and Dihydroquinazolinone Derivatives as Cytotoxic Agents. BMC Chem. 2022, 16, 35. [Google Scholar] [CrossRef]
- Dhananjaya, G.; Venkateshwarlu, R.; Madhubabu, M.V.; Raghunadh, A.; Murthy, V.N.; Reddy, S.P.; Anna, V.R.; Kapavarapu, R.; Pal, M. Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives as Potential Inhibitors of TNF-α. J. Mol. Struct. 2023, 1287, 135668. [Google Scholar] [CrossRef]
- Stájer, G.; Szabó, A.E.; Fülöp, F.; Bernáth, G.; Sohár, P. Stereochemical Studies, 106.–Saturated Heterocycles, 110 Synthesis of Methylene-bridged Partially Saturated Quinazolones. Chem. Ber. 1987, 120, 259–264. [Google Scholar] [CrossRef]
- Stájer, G.; Szabó, A.E.; Bernáth, G.; Sohár, P. Stereochemical Studies. Part 103. Saturated Heterocycles Part 107. Preparation of 3-Mono- and 2,3-Di-Substituted Pyrimidin-4(3H)-Ones in Retro–Diels–Alder Reactions. The Correct 1,2-Disubstituted Structure of the Compounds Previously Described as 2,3-Disubstituted Derivatives. J. Chem. Soc. Perkin Trans. 1 1987, 237–240. [Google Scholar] [CrossRef]
- Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; et al. Structure of Mpro from SARS-CoV-2 and Discovery of Its Inhibitors. Nature 2020, 582, 289–293. [Google Scholar] [CrossRef]
- Costanzo, M.J.; Yabut, S.C.; Zhang, H.-C.; White, K.B.; De Garavilla, L.; Wang, Y.; Minor, L.K.; Tounge, B.A.; Barnakov, A.N.; Lewandowski, F.; et al. Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase. Synthesis and Biological Evaluation of Novel Spirocyclic Piperidine Amide Derivatives. Bioorg. Med. Chem. Lett. 2008, 18, 2114–2121. [Google Scholar] [CrossRef]
- Lohning, A.E.; Levonis, S.M.; Williams-Noonan, B.; Schweiker, S.S. A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists. Curr. Top. Med. Chem. 2017, 17, 2023–2040. [Google Scholar] [CrossRef]
- Erickson, J.A.; Jalaie, M.; Robertson, D.H.; Lewis, R.A.; Vieth, M. Lessons in Molecular Recognition: The Effects of Ligand and Protein Flexibility on Molecular Docking Accuracy. J. Med. Chem. 2004, 47, 45–55. [Google Scholar] [CrossRef]
- Hsu, K.-C.; Chen, Y.-F.; Lin, S.-R.; Yang, J.-M. iGEMDOCK: A Graphical Environment of Enhancing GEMDOCK Using Pharmacological Interactions and Post-Screening Analysis. BMC Bioinf. 2011, 12, S33. [Google Scholar] [CrossRef] [PubMed]
- Dallakyan, S.; Olson, A.J. Small-Molecule Library Screening by Docking with PyRx. Chem. Biol. 2015, 1263, 243–250. [Google Scholar]
- Alamri, M.A.; Afzal, O.; Akhtar, M.J.; Karim, S.; Husain, M.; Alossaimi, M.A.; Riadi, Y. Synthesis, in Silico and in Vitro Studies of Novel Quinazolinone Derivatives as Potential SARS-CoV-2 3CLpro Inhibitors. Arabian J. Chem. 2024, 17, 105384. [Google Scholar] [CrossRef]
- Daina, A.; Michielin, O.; Zoete, V. SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep. 2017, 7, 42717. [Google Scholar] [CrossRef] [PubMed]
- Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings 1PII of Original Article: S0169-409X(96)00423-1. The Article Was Originally Published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv. Drug Deliv. Rev. 2001, 46, 3–26. [Google Scholar] [CrossRef] [PubMed]
- Veber, D.F.; Johnson, S.R.; Cheng, H.-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. J. Med. Chem. 2002, 45, 2615–2623. [Google Scholar] [CrossRef]
- Huey, R.; Morris, G.M.; Olson, A.J.; Goodsell, D.S. A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem. 2007, 28, 1145–1152. [Google Scholar] [CrossRef] [PubMed]
- Schrödinger, LLC. The PyMOL Molecular Graphics System, Version 2.5; Schrödinger, LLC.: New York, NY, USA, 2021. [Google Scholar]
- BIOVIA, Dassault Systèmes. BIOVIA Discovery Studio, 4.5; Dassault Systèmes: San Diego, CA, USA, 2021. [Google Scholar]
Entry | Catalyst | Solvent | Temp. (°C) | Time (h) | Yield a (%) |
---|---|---|---|---|---|
1 | NH4Cl | EtOH | Rt b | 24 | 29 c |
2 | NH4Cl | EtOH | 78 | 12 | 37 c |
3 | NH4Cl | 2M2B d | 100 | 9 | 35 |
4 | LiOH | EtOH | Rt b | 72 | 10 |
5 | LiOH | EtOH | 78 | 72 | 21 |
6 | p-TsOH | EtOH | Rt b | 168 | – |
7 | p-TsOH | EtOH | 78 | 168 | – |
8 | Amberlyst 15 | EtOH | Rt b | 120 | 20 c |
9 | Amberlyst 15 | EtOH | 78 | 10 | 25 c |
10 | I2 | EtOH | Rt b | 215 | – |
11 | I2 | EtOH | 78 | 14 | 35 |
12 | Alum | Glycerol | Rt b | 168 | – |
13 | Alum | Glycerol | 100 | 5 | – |
14 | Alum | 2M2B d | Rt b | 72 | – |
15 | Alum | 2M2B d | 100 | 168 | – |
16 | Alum | EtOH | 78 | 5 | 42 |
17 | Alum | Water | rt | 168 | – e |
18 | Alum | Water | 100 | 8 | – e |
Entry | Amide | Ketone | Time (h) | Product | Yield b (%) | de c (Major/Minor) |
---|---|---|---|---|---|---|
1 | 1a | 2a | 6 | 3a | 42 | 1:0 |
2 | 1a | 2b | 5 | 3b | 46 | 1:0 |
3 | 1a | 2c | 6 | 3c | 29 | 1:0 |
4 | 1a | 2d | 6 | 3d | 30 | 1:0 |
5 | 1b | 2a | 12 | 3e d | 35 | 1:0 |
6 | 1b | 2b | 10 | 3f | 37 | 1:0 |
7 | 1b | 2c | 24 | 3g d | 30 | 1:0 |
8 | 1b | 2d | 24 | 3h d | 28 | 1:0.3 |
9 | 1c | 2a | 5 | 3i | 45 | 1:0 |
10 | 1c | 2b | 5 | 3j | 42 | 1:0 |
11 | 1c | 2c | 6 | 3k | 24 | 1:0 |
12 | 1c | 2d | 6 | 3l | 38 | 1:0.4 |
13 | 1d | 2a | 14 | 3m | 31 | 1:0 |
14 | 1d | 2b | 20 | 3n | 24 | 1:0.4 |
15 | 1d | 2c | 24 | 3o e | 25 | 1:1 |
16 | 1d | 2d | 24 | 3p e | 34 | 1.3:1 |
Entry | Method | Product | Time (h) | Yield a (%) |
---|---|---|---|---|
1 | MW b | 3a | 0.5 | 85 |
2 | MW b | 3b | 1.5 | 83 |
3 | MW b | 3c | 1 | 85 |
4 | MW b | 3d | 2 | 71 |
5 | MW b | 3i | 1 | 70 |
6 | MW b | 3j | 1.5 | 65 |
7 | MW b | 3k | 2.5 | 59 |
8 | MW b | 3l | 2.5 | 60 |
9 | HSBM c | 3a | 6 | 45 |
10 | HSBM c | 3i | 6 | 45 |
11 | HSBM c | 3j | 6 | 37 |
12 | HSBM c | 3k | 4 | - |
13 | HSBM c | 3l* | 4 | - |
14 | CF d | 3a | 0.08 d | 70 |
15 | CF d | 3b | 0.08 d | 62 |
16 | CF d | 3d | 0.08 d | 70 |
17 | CF d | 3n* | 0.08 d | 52 |
18 | CF d | 3p* | 0.08 d | 44 |
Molecules | Estimated Total Energy (kcal/mol) a | Binding Affinity (kcal/mol) b | Active Site Residue Chain A c |
---|---|---|---|
3a | −62.559 | −7.8 | LEU141, SER144, CYS145 |
3b | −63.773 | −8.1 | LEU141, SER144, CYS145 |
3c | −59.252 | −8.2 | SER144, CYS145 |
3d | −64.985 | −8.1 | LEU141, GLY143, SER144, CYS145 |
3e | −55.856 | −8.6 | GLY143, SER144, CYS145 |
3f | −58.697 | −7.7 | GLY143, SER144, CYS145 |
3g | −57.707 | −7.7 | LEU141, GLY143, SER144, CYS145 |
3i | −64.442 | −7.3 | SER158 |
3j | −65.518 | −7.4 | GLY143, HIS164 |
3k | −57.736 | −7.1 | GLY143, HIS164 |
3m | −56.195 | −7.8 | HIS144 |
Molecules | Estimated Total Energy (kcal/mol) a | Binding Affinity (kcal/mol) b | Residue Chain A c |
---|---|---|---|
3a | −100.957 | −8.7 | HIS42, ARG153 |
3b | −100.858 | −9.0 | ASP147, GLN206 |
3c | −97.333 | −8.6 | HIS42, ASP147 ARG153, GLN206 |
3d | −100.224 | −9.1 | HIS42, ASP146, GLN206 |
3e | −87.828 | −8.6 | TRP145, GLN206 |
3f | −98.296 | −8.7 | HIS42, TYR81, TRP145, ASP147, GLN206 |
3g | −95.208 | −8.7 | HIS42, TYR81, TRP145, ASP147, GLN206 |
3i | −100.404 | −8.0 | HIS42, ASP147 |
3j | −100.032 | −8.3 | HIS42, ARG153 |
3k | −97.9363 | −7.5 | TYR39, TYR81, ARG153, LEU154 |
3m | −86.146 | −8.6 | HIS42, TYR81, TRP145, ASP147 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Faragó, T.; Mészáros, R.; Wéber, E.; Palkó, M. Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives. Molecules 2024, 29, 5112. https://doi.org/10.3390/molecules29215112
Faragó T, Mészáros R, Wéber E, Palkó M. Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives. Molecules. 2024; 29(21):5112. https://doi.org/10.3390/molecules29215112
Chicago/Turabian StyleFaragó, Tünde, Rebeka Mészáros, Edit Wéber, and Márta Palkó. 2024. "Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives" Molecules 29, no. 21: 5112. https://doi.org/10.3390/molecules29215112
APA StyleFaragó, T., Mészáros, R., Wéber, E., & Palkó, M. (2024). Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives. Molecules, 29(21), 5112. https://doi.org/10.3390/molecules29215112